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Metformin, a biguanide, has been available in the US for the treatment of type 2 diabetes mellitus for nearly 8 years. Over this period of time, it has become the most widely prescribed antihyperglycaemic agent. Its mechanism of action involves the suppression of endogenous glucose production, primarily by the liver. Whether the drug actually has an insulin sensitising effect in peripheral tissues, such as muscle and fat, remains somewhat controversial. Nonetheless, because insulin levels decline with metformin use, it has been termed an 'insulin sensitiser'. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular outcomes in patients with diabetes. Cardiovascular disease, impaired glucose tolerance and the polycystic ovary syndrome are now recognised as complications of the insulin resistance syndrome, and there is growing interest in the management of this extraordinarily common metabolic disorder. While diet and exercise remain the cornerstone of therapy for insulin resistance, pharmacological intervention is becoming an increasingly viable option. We review the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits it provides over and above its effect on glucose levels alone. We also discuss its potential role for a variety of insulin resistant and prediabetic states, including impaired glucose tolerance, obesity, polycystic ovary syndrome and the metabolic abnormalities associated with HIV disease.
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PMID:Metformin: new understandings, new uses. 1293 Jan 61

The study population in this report by Lin et al. was ob/ob mice that have an inherited genetic deficiency of the appetite-suppressing hormone leptin. These mice develop hyperinsulinemia, insulin resistance, and fatty livers. Compared with their lean littermates and wild-type C57BL-6 mice, ob/ob mice have hepatomegaly. In this study, the authors compared three different groups of adult mice (aged 8-10 wk), including male ob/ob C57BL-6 mice, their lean littermates, and wild-type C57BL-6 mice of the same age and sex. The primary purpose of this study was to test the efficacy of metformin for treatment of fatty liver disease in obese, ob/ob mice that develop hyperinsulinemia or insulin resistance and fatty livers. Metformin therapy was found to eliminate fatty liver disease in this model. The potential mechanisms of the action of metformin were the inhibition of hepatic tumor necrosis factor (TNF)alpha and several TNF-inducible responses, which are likely to promote hepatic steatosis and necrosis. In these experiments, ob/ob mice were divided into three treatment groups. Group 1 consisted of eight mice that were treated with metformin and permitted to consume a nutritiously replete liquid mouse diet ad libitum. Mice in group 2 (n = 8) did not receive metformin but were pair-fed the same volume of liquid diet that the mice in the metformin-treated group had consumed on the previous day. Obese ob/ob mice in group 3 (n = 4) and lean mice received no metformin, as with the mice in group 2, but were permitted to consume the liquid diet ad libitum. Liquid diet was given to facilitate accurate daily comparison of food intake among the various treatment groups. All mice were weighed at the beginning of the study and weekly thereafter until killed and then sera, fat, and liver tissues were collected. Tissues were either fixed in buffered formalin and processed from the deceased mice for histology or snap frozen in liquid nitrogen and stored until RNA and proteins were isolated. The feeding protocol was repeated with a second group of 18 ob/ob mice. After 4 wk, hepatocytes were obtained by in situ liver perfusion with collagenase and assayed for cellular adenosine triphosphate (ATP) content. In each experiment, hepatocytes isolated from 3 mice from each treatment group were suspended in a medium and pooled for subsequent analysis to evaluate cell viability, determine the number of obtained cells, and to assay cellular ATP content. These experiments were repeated using another 3 mice from each treatment group, so that analysis of hepatocytes took place from six ob/ob mice in each feeding group.Hepatic steatosis was decreased significantly only in the metformin-treated group. The authors found that metformin's beneficial effect on the fatty liver disease of mice was not due to its ability to constrain hyperphagia, nor due to decreased caloric ingestion, because the daily caloric intakes of the metformin-treated mice and the pair-fed control mice were virtually identical. These caloric intakes were consistently approximately 20% less than that of another obese control group that was permitted to consume diet ad libitum. The authors also observed no significant effect of metformin on serum glucose concentration from fed, ob/ob mice. Metformin is known to reduce hyperinsulinemia by about 40% in both of these obese hyperinsulinemic and insulin-resistant rodent strains. In conclusion, Lin et al. documented that metformin improves fatty liver disease and reverses hepatomegaly, steatosis, and aminotransferase abnormalities in mice. In addition, the authors suggest that metformin might inhibit dieting-induced redistribution of lipid from the liver to adipose tissue depots. In summary, this study identifies a potential treatment for fatty liver disease in humans.
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PMID:Current biochemical studies of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis suggest a new therapeutic approach. 1449 93

Polycystic ovary syndrome (PCOS) is a common disorder among reproductive-age women, yet the diagnosis may be overlooked during adolescence. Although the clinical and metabolic features are similar to those found in adult women, it can be difficult to distinguish the young woman with PCOS from a normal adolescent. Irregular menses, anovulatory cycles, and acne are not uncommon in adolescent women. Adolescents with a history of premature pubarche, a family history of PCOS, Caribbean-Hispanic and African-American ancestry, and/or obesity are at risk for PCOS and deserve close surveillance. The laboratory evaluation of the adolescent with suspected PCOS or hyperandrogenism should be individualized based on the history, symptoms, and examination findings. The cornerstone of management of PCOS in adolescence includes either a combination oral contraceptive or progestin. Consideration of insulin-sensitizing agents, antiandrogens, topical treatments for acne, and various treatments for hair removal are dependent on the patient's symptoms and concerns. Healthy eating, regular exercise, and for the overweight adolescent, weight reduction, are encouraged to reduce the risk of cardiovascular disease and type II diabetes mellitus. Numerous studies have shown that weight loss and exercise decrease androgen levels, improve insulin sensitivity, and lead to the resumption of ovulation. Although initial studies suggest that Metformin may be particularly useful for treating the PCOS adolescent with insulin resistance and obesity, additional studies are needed to determine the efficacy and long-term outcome. Management of the adolescent with PCOS is challenging and requires a supportive, multidisciplinary team approach for optimal results.
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PMID:Polycystic ovary syndrome in adolescence. 1464 9

Burgeoning obesity is increasing the prevalence of type II diabetes mellitus. As a consequence, there will be an even greater burden of cardiovascular disease, end-stage renal disease, blindness, and lower extremity amputations. If diagnosed, impaired glucose tolerance presents an opportunity for intervention that potentially could delay or prevent the development of diabetes. Recent prospective studies document the effectiveness of exercise and weight reduction in preventing diabetes. Metformin is less effective than intense lifestyle interventions. Acarbose, losartan, orlistat, pravastatin, ramipril, and hormone replacement therapy are associated with lower rates of the development of diabetes. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial were designed to assess not only the prevention of diabetes but also the impact on cardiovascular morbidity and mortality.
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PMID:Preventing type II diabetes mellitus. 1505 49

Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus, but it is also present in up to 25% of healthy nonobese individuals. The molecular mechanisms causing insulin resistance are not yet fully understood. Recently, overexpression of several potential inhibitors of the insulin receptor tyrosine-kinase activity, a key step in insulin signaling, has been described in insulin-resistant subjects . PC-1 is expressed in many tissues and inhibits insulin signaling either at the level of the insulin receptor or downstream at a postreceptor site. An elevated PC-1 content in insulin target tissues may play an important role in the development of insulin resistance in obesity and type 2 diabetes mellitus. A polymorphism in PC-1 has been demonstrated to be associated with insulin resistance. This was a DNA polymorphism in exon 4 that causes an amino acid change from lysine to glutamine at codon 121 (K121Q). PC-1 121Q allele might predispose independently of other well established risk factors for early myocardial infarction. Testing for the PC-1 K121Q polymorphism might be valuable in patients with a family history of atherosclerotic vascular disease and myocardial infarction. There is growing evidence that genetic factors play an important role in the development of diabetic nephropathy (DN). Efforts to identify these factors rely primarily on the candidate gene approach; candidate genes for insulin resistance may be considered candidates for DN as well. In a stratified analysis according to duration of diabetes, the risk of early-onset end-stage renal disease (ESRD) for carriers of the Q variant was 2.3 times that for noncarriers. The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. Women with GDM have an increased PC-1 content and excessive phosphorylation of serine/threonine residues in muscle insulin receptors. The postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life. Although widely explored, the true cause of insulin resistance in uremic patients is not entirely elucidated yet. During the last decade it was found that erythropoietin (EPO) therapy, used for correction of anemia in patients with end stage renal failure, ameliorates insulin resistance. An increased lymphocyte PC-1 activity over control was found in hemodialysis patients. A two-month EPO therapy significantly decreased PC-1 activity to the control values, suggesting that an effect on PC-1 expression could be implicated in the amelioration of insulin resistance in uremic patients treated with EPO. Current investigations implicate that therapeutic modification of PC-1 expression would be of great benefit for insulin-resistant type 2 diabetics. Metformin, a biguanide oral antidiabetic agent, was shown to affect insulin resistance by decreasing enzymatic activity of overexpressed PC-1 molecules in obese type 2 diabetics. Thiazolidinedione (TZD) insulin-sensitizing drugs are a class of compounds that improve insulin action in vivo. Treatment of patients with TZDs seems to have a beneficial effect on most, if not all, components of metabolic syndrome. TZDs have also been used in the treatment of nondiabetic human insulin-resistant states, and have demonstrated an improvement in insulin sensitivity. Although much remains to be learned about PPAR gamma receptor and TZD action, the advent of TZD insulin-sensitizing agents has an enormous impact on our understanding of insulin resistance. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms.
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PMID:Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. 1520 35

Type 2 diabetes mellitus, once considered a disease only of adults, is now being diagnosed at an increasingly alarming rate in children. It is still unclear whether the presentation, risk factors, course, and treatment of the disease are the same in children as they are in adults. Pediatric-specific prevalence is being linked to obesity and inactivity, and risk factors include being overweight, family history of the disease, and conditions of insulin resistance such as puberty. Although the clinical presentations of types 1 and 2 diabetes often are different, they can be similar, which makes it difficult to differentiate between the two. Metformin is the only drug approved for the treatment of type 2 diabetes in children, but other drugs are being studied. Prevention is essential. It is critical that health care professionals and the public are educated about this disease and that studies are conducted that focus on children with type 2 diabetes.
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PMID:Type 2 diabetes mellitus in the pediatric population. 1530 51

There exist controversial reports regarding the differences in phospholipid fatty acids in type 2 diabetic and obese patients as compared to controls. The study was aimed at assessing the combined effect of type 2 diabetes and obesity on the fatty acid composition of plasma phospholipids. The experimental group consisted of 23 Belgian obese type 2 diabetics on Metformin. Two control groups were used: healthy lean and obese individuals in the same BMI range as the diabetics. Plasma phospholipids were isolated and their fatty acids and vinyl ether moieties were determined. Significance was set at P < 0.01. Plasma phospholipid fatty acids and plasmalogen-derived dimethyl acetals in diabetics deviated in many respects from these of lean controls but were not significantly different from those of obese non-diabetic patients. Therefore, the deviations of the fatty acid pattern of plasma phospholipids in type 2 diabetes may be attributed to obesity rather than to diabetes itself.
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PMID:Obese type 2 diabetics and obese patients have comparable plasma phospholipid fatty acid compositions deviating from that of healthy individuals. 1538 Aug 17

Metformin (dimethyl-biguanide) is an oral antidiabetic drug, which decreases hepatic glucose production (gluconeogenesis) and increases peripheral glucose uptake by muscles. Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients, offering a selective pathophysiological approach by its effect on insulin resistance. It has been shown in a number of studies to improve clinical outcomes in type 2 diabetic patients. It has been demonstrated in a number of studies that metformin has multiple biological effects - it has been shown to have platelet antiaggregating effects, to reduce the rate of formation of advanced glycation end products (AGEs) and to decrease the cellular oxidative reactions, thus demonstrating the antioxidant effects of the drug, which may largely explain its vascular protective effect. A number of studies have established the favorable effect of metformin on body weight, insulin resistance, hyperinsulinaemia, lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides), arterial hypertension, fibrinolysis, endothelial dysfunction. Thus metformin appears to have a broad set of pharmacological properties, making the drug potentially applicable even in nondiabetic situations such as obesity, extreme insulin resistance with acanthosis nigricans, polycystic ovary syndrome, etc. Metformin has been demonstrated in the Diabetes Prevention Program to be a drug with great potential in preventing the conversion of IGT to type 2 diabetes. Thus, metformin appears to be a drug with multiple therapeutic effects far beyond its effect on lowering blood glucose in diabetes mellitus.
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PMID:Current indications for metformin therapy. 1552 5

Metformin is an anti-diabetic drug with anorexigenic properties. The precise cellular mechanisms of its action are not entirely understood. Adipose tissue has recently been recognized as an important endocrine organ that is pivotal for the regulation of insulin resistance and energy homeostasis. Due to its thermogenic capacity brown adipose tissue contributes to the regulation of energy metabolism and is an attractive target tissue for pharmacological approaches to treating insulin resistance and obesity. Leptin is the prototypic adipocyte-derived hormone inducing a negative energy balance. We investigated effects of metformin on adipocyte metabolism, signalling, and leptin secretion in a brown adipocyte model. Metformin acutely stimulated p44/p42 mitogen-activated protein (MAP) kinase in a dose- (3.2-fold at 1 mmol/l, P< 0.05) as well as time-dependent (3.8-fold at 5 min, P< 0.05) manner. This stimulation was highly selective since phosphorylation of intermediates in the stress kinase, janus kinase (JAK)-signal transducer and activator of transcription (STAT), and phosphatidylinositol (PI) 3-kinase signalling pathways such as p38 MAP kinase, STAT3, and Akt was unaltered. Furthermore, chronic metformin treatment for 12 days dose-dependently inhibited leptin secretion by 35% and 75% at 500 mumol/l and 1 mmol/l metformin respectively (P< 0.01). This reduction was not caused by alterations in adipocyte differentiation. Moreover, the impairment in leptin secretion by metformin was reversible within 48 h after removal of the drug. Pharmacological inhibition of p44/p42 MAP kinase prevented the metformin-induced negative effect on leptin secretion. Taken together, our data demonstrate direct acute effects of metformin on adipocyte signalling and endocrine function with robust inhibition of leptin secretion. They suggest a selective molecular mechanism that may contribute to the anorexigenic effect of this antidiabetic compound.
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PMID:Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes. 1553 18

Metformin reduces the incidence of progression to type 2 diabetes in humans with obesity or impaired glucose tolerance. We used an animal model to investigate whether metformin could prevent acute lipid-induced insulin resistance and the mechanisms involved. Metformin or vehicle was administered to rats daily for 1 week. Rats were studied basally, after 3.75 h of intralipid-heparin or glycerol infusion, or after 5 h of infusion with a hyperinsulinemic-euglycemic clamp between 3 and 5 h. Metformin had no effect on plasma triacylglycerol or nonesterified fatty acid concentrations and did not alter glucose turnover or gluconeogenic enzyme mRNA after lipid infusion. However, metformin normalized hepatic glucose output and increased liver glycogen during lipid infusion and clamp. Basal liver (but not muscle or fat) AMP-activated protein kinase activity was increased by metformin (by 310%; P < 0.01), associated with increased phosphorylation of acetyl CoA carboxylase. Postclamp liver but not muscle phosphorylated/total Akt protein was increased, whereas basal c-Jun NH2-terminal kinase-1 and -2 protein expression were reduced (by 39 and 53%, respectively; P < 0.05). Metformin also increased hepatic basal IkappaBalpha levels (by 260%; P < 0.001) but had no effect on tyrosine phosphorylation or expression of insulin receptor substrate-1 (IRS-1). In summary, metformin opposes the development of acute lipid-induced insulin resistance in the liver through alterations in multiple signaling pathways.
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PMID:Metformin prevents the development of acute lipid-induced insulin resistance in the rat through altered hepatic signaling mechanisms. 1556 58


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